This application requests continuation of a Multi-center AIDS Cohort Study (MACS) Pathogenesis Research Laboratory (MPRL) which consists of a consortium of investigators at John Hopkins University, the University of Pittsburgh, and the University of Washington. The scientific agenda for this application is based on the accomplishments of the current funding period, especially the finding of an ordered cascade of events which characterized the 3-4 years before the onset of clinically defined AIDS in those HIV-1 infected MACS participants who progressed to advanced HIV-1 disease. The hallmarks of this cascade included increases in viral intra-timepoint diversity and divergence from the founder strain, which then stabilized or declined; detection of X4 (CXCR4-utilizing) strains of HIV-1 in the peripheral blood, at least transiently; and loss of normal of circulating total T (CD3+) lymphocytes (failure of T cell homeostasis), including preferential loss of naive CD4+ T cells. The specific aims of the present application, therefore, are: 1) To confirm this cascade and the stages of asymptomatic HIV-1 infection it defines; 2) To determine the specific mutations and patterns of evolution required for outgrowth of X4 viruses; 3) To elucidate the role of CD8+ T cells in controlling HIV replication and evolution; and 4) To use the above information to determine the impact of virologic and immunologic status at the initiation of highly active anti-retroviral therapy (HAART) on the response to HAART. Both retrospective and real-time study designs will be used, to take advantage of the excellent MACS cohort follow-up as well as repository of lymphocyte, plasma, and clinical data. Results from these studies should help to improve understanding of a) mechanisms influencing the rate of HIV-1 disease progression and b) optimal ways to balance the benefits and risks of HAART.